Sunday, July 18, 2010

Dr. Fauci: Stop operating like a bureaucrat and start acting like a genius

Larry Kramer to Tony Fauci, asking him to lead on AIDS cure research, this morning: "Stop operating like a bureaucrat and start acting like a genius." Fauci's emailed response is below.

Controlling and Ultimately Ending the HIV/AIDS Pandemic
A Feasible Goal

Gregory K. Folkers, MS, MPH; Anthony S. Fauci, MD
JAMA. 2010;304(3):350-351. doi:10.1001/jama.2010.957

It has been nearly 3 decades since the recognition of AIDS1-2 and the discovery of its etiologic agent, the human immunodeficiency virus (HIV).3 Despite numerous scientific advances and major successes in the areas of prevention and treatment, HIV/AIDS continues to exact an enormous toll.4 Nonetheless, controlling and ultimately ending the HIV/AIDS pandemic is feasible. Such a goal will require 3 overarching elements: increasing HIV testing and availability of antiretroviral therapy (ART) for HIV-infected individuals; curing a sizeable proportion of HIV infected individuals, such that they no longer require lifelong therapy; and preventing new infections, using both previously proven strategies and a new generation of prevention tools.
Scaling Up Delivery of Proven Therapies

The development of ART has been the one of the greatest accomplishments of basic and translational research: approximately 30 anti-HIV agents are licensed and evidence-based guidelines have been developed for their optimal use.5-6 Combination ART with at least 3 drugs has resulted in substantial reductions in morbidity and mortality in both rich and poor countries. Antiretroviral therapy has been simplified to the point where treatment with a single, multidrug pill once a day is possible with generally manageable adverse effects.5-6 With improvements in ART, the estimated life expectancy of certain HIV-infected patients now approaches that of uninfected individuals.7-8 Antiretroviral therapy also has proven efficacious in HIV prevention, reducing the risk of mother-to-child transmission and serving as postexposure prophylaxis for individuals exposed to HIV.5-6 A recent study of HIV-serodiscordant couples in 7 African countries found that treatment of the infected partner reduced the risk of HIV transmission to the uninfected partner by 92%.8 In addition, cohort studies have shown that expanded treatment in communities was associated with a decrease in the number of new infections.10-11
More than 4 million persons in low- and middle-income countries as well as approximately 1 million persons in the developed world are now receiving ART.4, 6 Still, there are far more individuals who need but are not receiving these lifesaving medicines. Using the CD4 cell count stratum recommended by most guidelines for initiating therapy (350/uL), only approximately 30% of individuals who need ART in low- and middle-income countries are receiving it.6 Meanwhile, for every person who receives therapy in these countries, 2 to 3 individuals are newly infected.4 Even in certain areas of the United States, access to HIV testing, treatment, and care is suboptimal. Approximately 20% of the 1.1 million HIV-infected individuals in the United States are unaware of their infection, and many HIV-infected individuals learn of their infection and access treatment only when presenting with advanced HIV disease.12 In 2010, that is unacceptable.
It is a moral and public health imperative that the global community strives to achieve access to ART for all who require such therapy according to established guidelines. Operational research must be vigorously pursued to identify the most efficient and cost-effective methods to deliver high-quality HIV treatment and care. Yet, even with increased funding and efficiencies, the stark reality is that it is extremely unlikely the financial or the operational capacity will be available to reach and treat indefinitely everyone in the world who requires ART. Therefore, considerations related to a cure and prevention loom large.

Curing Existing Infections

Despite considerable success in suppressing viremia and preventing disease progression in HIV-infected individuals, it has not been possible to induce permanent remission of disease in the absence of therapy. This is because HIV has the unique ability to shield itself from the immune system and from ART in protected cellular sanctuaries. These persistent reservoirs of infection are major obstacles to curing HIV infection. An increasing research effort is directed at determining the precise mechanisms of HIV persistence and using this information to develop novel interventions to eliminate or permanently suppress these viral reservoirs. The effects of a cure would be significant for individuals and society. Patients would be spared the cumulative effects of drug toxicities; a "cured" individual would have minimal risk for transmitting the virus; and resources would be made available for other services, not only HIV-related, but also those directed at an overall strengthening of health care systems.

Preventing New Infections

HIV infection is eminently preventable, and numerous prevention strategies (such as condom use, education/behavioral modification, screening of blood supplies, adult male circumcision, needle exchange programs, ART to prevent mother-to-child transmission, and prevention and treatment of drug and alcohol abuse) have a strong evidence base.4 However, these and other proven interventions are accessible only to a minority of persons who need them globally.4 Prevention programs using proven tools must be substantially scaled up, refined, enhanced, and made more cost-effective. In addition, it is imperative to move toward a more comprehensive and multifaceted approach to HIV prevention. "Combination prevention" should become established in the HIV prevention lexicon, similar to "combination therapy."
Given the effect of ART on reducing HIV viremia, and the direct relationship between viral load and the efficiency of HIV transmission,13 the use of ART as a means of preventing transmission is central to the goal of combination prevention. The development of topical microbicides—compounds formulated in gels, creams, films, or vaginal rings placed in the vagina or rectum to block HIV transmission—is now focused largely on antiretroviral-based strategies. Several large studies of pre-exposure prophylaxis for HIV prevention, which involves providing ART to HIV-negative individuals who are at high risk of HIV infection, are currently underway.
Other approaches to using ART as prevention fall under the rubric of "test and treat." In various models, notably by Granich et al,14 a program of universal, voluntary, annual HIV testing and immediate treatment of those who test positive has been proposed as a potential means to end the pandemic over a few decades. This approach, which is based on a number of optimistic assumptions, may not be feasible in the real world; however, some version of an expanded program of aggressive testing and treatment likely will be an important tool as part of a broader combination prevention initiative. In this regard, the feasibility of such an approach is actively being pursued in the research agendas of the National Institutes of Health and other funding agencies.
Finally, the most powerful prevention tool would be a safe and effective HIV vaccine. In 2009, a large phase 3 clinical efficacy trial in Thailand of a prime/boost vaccine regimen provided the first, albeit modest, signal that a vaccine could prevent HIV infection.15 This study provided important new clinical research leads that are being pursued aggressively, along with basic research data that will be useful in addressing fundamental issues in HIV vaccinology, such as the identification of neutralizing epitopes on the HIV envelope and use of these epitopes as immunogens through structure-based vaccine design.
Controlling and ending the global HIV/AIDS pandemic is feasible; however, it will require a multifaceted global effort involving expanded testing, treatment, striving for a cure in at least a proportion of infected individuals, and a comprehensive combination prevention program. No single nation or organization can accomplish this. A truly global commitment and effort are essential.


Corresponding Author: Anthony S. Fauci, MD, National Institute of Allergy and Infectious Diseases, Bldg 31, Room 7A-03, 31 Center Dr, MSC 2520, National Institutes of Health, Bethesda, MD 20892 ( ).
Financial Disclosures: None reported.
Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.
Author Affiliations: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.


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